The present invention is directed to novel and advantageous processes for the synthesis of tigogenin beta-cellobioside and to certain novel intermediates used in these processes.
Tigogenin beta-cellobioside is a known compound having utility in the treatment of hypercholesterolemia and atherosclerosis (Malinow, U.S. Pat. Nos. 4,602,003 and 4,602,005; Malinow et al. Steroids, vol. 48, pp. 197-211, 1986). Each patent discloses a different synthesis of this compound from beta-cellobiose octaacetate; the first via the glycolyl bromide heptaacetate which is coupled with tigogenin in the presence of silver carbonate, and finally hydrolyzed; and the second direct stannic chloride catalyzed coupling of the octaacetate with tigogenin in methylene chloride, again followed by hydrolysis. In Malinow et al., reaction of cellobiose octaacetate with titanium tetrabromide gave the glycosyl bromide heptaacetate, which was coupled with tigogenin by means of mercuric cyanide, and then hydrolyzed. All of these methods have serious drawbacks for producing bulk material. A desirable goal, met by the present invention, has been to devise synthetic methods which avoid toxic and/or expensive reagents, and which cleanly produce the desired tigogenin betacellobioside, avoiding tedious and expensive purification steps.
Schmidt, Angew. Chem. Int. Ed. Engl., v. 25, pp. 212-235 (1986) has reviewed the synthesis and reactions of O-glycosyl trichloroacetimidates formed by the reaction of sugars possessing a 1-OH group (but with other hydroxy groups protected, e.g., by benzyl or acetyl) with trichloroacetonitrile in the presence of a base. There is preferential formation of the alpha-anomer when NaH is used as base, and preferential formation of the beta-anomer when the base is K.sub.2 CO.sub.3. The alpha anomer of tetrabenzylglucosyl trichloroacetimidate when coupled with cholesterol gave anomeric mixtures which varied with catalyst (p-toluenesulfonic acid or boron trifluoride etherate) and temperature (-40.degree. to +20.degree. C.). On the other hand, both the alpha and beta anomers of tetraacetylglucosyl analog reportedly yield exclusively beta-anomeric products.